Ranolazine

Absorption

The time to reach peak serum concentration is quite variable but has been observed to be in the range of 2-6 hours, with steady-state within 3 days. The FDA indicates a Tmax of 3-5 hours. The average steady-state Cmax is about 2600 ng/mL. Absorption of ranolazine is not significantly affected by food consumption. The bioavailability of ranolazine taken in the tablet form compared to that from a solution of ranolazine is about 76%.

Toxicity

The reported LD50 of oral ranolazine in the rat is 980 mg/kg. High oral doses of ranolazine have led to dizziness, nausea, and vomiting. These effects have been shown to be dose related. High intravenous doses can cause diplopia, confusion, paresthesia, in addition to syncope. In the case of an overdose, provide supportive therapy accompanied by continuous ECG monitoring for QT interval prolongation.

Description

Ranolazine is an orally available, extended release drug for the treatment of chronic angina in patients who have failed to respond to prior angina therapy. Chronic stable angina (CSA) is a common symptom of coronary artery disease wherein plaques in the coronary vasculature restrict blood flow to the heart, which in turn leads to insufficient oxygenation of the heart, typically during physical exertion or emotional stress. A vast majority of the existing anti-anginal and anti-ischemic therapies aim to correct the imbalance between myocardial oxygen demand and supply through mechanisms that produce reductions in heart rate or blood pressure.

Chemical properties

White Solid

Originator

Roche Bioscience (US)

The Uses of Ranolazine

Ranolazine is an anti-ischemic agent which modulates myocardial metabolism. Antianginal.

The Uses of Ranolazine

antianginal, antiischemic

Indications

Ranolazine is indicated for the treatment of chronic angina. It can be used alone or in conjunction with nitrates, beta-blockers, angiotensin receptor blockers, anti-platelet drugs, calcium channel blockers, lipid-lowering drugs, and ACE inhibitors.
Ranolazine has also been used off-label for the treatment of certain arrhythmias, including ventricular tachycardia, however, this use is not strongly supported by scientific evidence. Ranolazine has also been studied for the treatment of acute coronary syndrome, microvascular coronary dysfunction, arrhythmia, and glycemic control, which are not yet approved indications.

Background

Chronic angina is a common cardiovascular condition affecting millions worldwide and causes significant disability while interfering with daily activities. Ranolazine is a well-tolerated piperazine derivative used for the management of this condition, offering relief from uncomfortable and debilitating symptoms. With a mechanism of action different from drugs used to treat the same condition, ranolazine is a promising anti-anginal therapy. It was originally approved by the FDA in 2006.

What are the applications of Application

Ranolazine is an anti-ischemic agent which inhibits late sodium currents

Definition

ChEBI: N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl}acetamide is an aromatic amide obtained by formal condensation of the carboxy group of 2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl}acetic acid with the amino group of 2,6-dimethylaniline. It is a monocarboxylic acid amide, an aromatic amide, a N-alkylpiperazine, a secondary alcohol and a monomethoxybenzene.

brand name

Ranexa (Sensus).

General Description

Ranolazine, N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl]acetamide (Ranexa), is an antianginal medication thatwas approved by the Food and Drug Administration (FDA)in January 2006 for the treatment of chronic angina.Ranolazine is believed to elicit its effects by altering thetranscellular late sodium current. This, in turn, alters thesodium-dependent calcium channels during myocardial ischemia.Thus, ranolazine indirectly prevents the calciumoverload that is associated with cardiac ischemia.Ranolazine is metabolized by the cytochrome CYP3A enzymesin the liver.

Pharmacokinetics

Ranolazine exerts both antianginal and ischemic effects independent from lowering heart rate or blood pressure. It blocks IKr, the rapid portion of the delayed rectifier potassium current, and prolongs the QTc interval in a dose-dependent fashion. The Ikr is important for cardiac repolarization. Ranolazine exerts its therapeutic effects without negative chronotropic, dromotropic, or inotropic actions neither at rest, nor during exercise.

Clinical Use

Add on therapy for angina

Synthesis

Two syntheses, one from the inventors at Roche and other from a group in Hungary, of Ranolazine have been described in the patent literature. The original synthesis is highlighted in the Scheme. Reaction of 2,6-dimethylaniline 46 with chloroacetyl chloride (47) in the presence of triethylamine for 4h at 0oC gave amide 48 in 82% yield. This chloro amide 48 was reacted with piperazine in refluxing ethanol for 2 h to give piperazinyl amide 50. Reaction of amide 50 with epoxide intermediate 53, prepared by reacting 2-methoxy phenol 51 with epichlorohydrin, in refluxing isopropanol for 3 h followed by treatment with HCl/methanol gave ranolazine dihydrochloride (VII) in 73% yield.

Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: avoid with disopyramide.
Antibacterials: concentration possibly increased by clarithromycin and telithromycin - avoid concomitant use; concentration reduced by rifampicin - avoid.
Antifungals: concentration increased by ketoconazole and possibly itraconazole, posaconazole and voriconazole - avoid.
Antivirals: concentration possibly increased by atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, ritonavir, saquinavir and tipranavir - avoid.
Beta-blockers: avoid with sotalol.
Ciclosporin: concentration of both drugs possibly increased.
Grapefruit juice: concentration of ranolazine possibly increased - avoid.
Statins: concentration of simvastatin increased - maximum dose of simvastatin is 20 mg.
Tacrolimus: concentration of tacrolimus increased.

Metabolism

Ranolazine is rapidly heavily metabolized in the liver an gastrointestinal tract through the activity of the CYP3A4 enzyme with minor contributions from CYP2D6. More than 40 ranolazine metabolites have been found in plasma and more than 100 metabolites have been identified in the urine.
Ranolazine and some of its metabolites are known to weakly inhibit CYP3A4. However, the activity of the metabolites of ranolazine has not been fully elucidated.

Metabolism

Extensively metabolised in the gastrointestinal tract and liver. Four main metabolites have been identified.
Approximately 75% of a dose is excreted in the urine with the remainder in the faeces.